The invention relates to apoptosis in cells, particularly cell involved in fertility.
Apoptosis is a fundamental process of cell death required for the elimination of unwanted cells in multicellular organisms and involves an ordered cascade of events leading to hallmark morphological changes including nuclear condensation, chromosome laddering, and membrane blebbing. In one specific example, apoptosis plays a prominent role during all stages of sperm development. Spermatogenesis is a process that results in the generation of mature sperm cells from primary germ cells, and some of the events affected by apoptosis include the elimination of unwanted cells and the prevention of the death of those cells destined to become functional sperm (Hsueh et al., Recent Prog. Horm. Res. 51: 433, 1996; Furuchi et al., Development 122: 1703, 1996).
Much of the current knowledge of the biochemical pathways involved in apoptosis comes from the study of viruses. The baculoviral proteins involved in apoptosis, CpIAP and OpIAP, are characterized by two amino terminal cys/his motifs (Xaa.sub.3 -R-Xaa.sub.20-23 -G-Xaa.sub.11 -C-Xaa.sub.2 -C-Xaa.sub.16 -H-Xaa.sub.6 -C-Xaa.sub.3) (SEQ ID NOS:6-9) and a carboxy terminal C-Xaa.sub.2 -C-Xaa.sub.11 -C-Xaa-H-Xaa.sub.3 -C-Xaa.sub.2 -C-Xaa.sub.6 -C-Xaa.sub.2 -C RING zinc finger motif (SEQ ID NO:10) reviewed in Clem et al., Cell Death Differ. 3: 9, 1996). The two amino terminal motifs, termed Baculovirus IAP Repeat (BIR) domains, are the hallmark of the IAP family of proteins and are present as two or three copies in all IAP members discovered to date.
The first mammalian IAP (inhibitor of apoptosis protein), NAIP, was identified during a positional cloning effort seeking candidate genes for spinal muscular atrophy (Roy et al., Cell 80: 167, 1995). Following the identification of NAIP, three other human IAPs, HIAP-1, HIAP-2, and XIAP (Liston et al., Nature 379: 349, 1996), and their murine homologues MIAP-1, MIAP-2, and MIAP-3 (Farahani et al., Genomics 42: 514, 1997), have been reported. In addition, two Drosophila IAPs, DIAP-1 and DIAP-2, and one chicken IAP, ITA have been described (see Liston et al., Apoptosis 2: 423, 1997). A structural comparison of these IAPs is shown in FIG. 1.
The physiological role of XIAP remains elusive. Recent work has demonstrated that XIAP directly inhibits two of the caspases, namely caspase-3 (also known as CPP32, Apopain, or YAMA) and caspase-7 (Devereaux et al., Nature 388: 300, 1997).